Available vehicles for the parenteral administration of water-insoluble compounds often produce undesirable side-effects such as hemolysis, thrombophlebitis, or blood coagulation. Liposomes and oil-in-water emulsions have been promoted as potential carriers for fat-soluble materials which minimize such undesirable side-effects. However, many problems with stability and drug loading capacity have been reported using either of these delivery systems.
The use of liposomes as drug delivery systems has been known for some time, and comprehensive review articles on their properties and clinical applications are available; see, e.g., Barenholz and Amselem, in "Liposome Technology", 2nd ed., G. Gregoriadis, ed., CRC press, 1992; Lichtenberg and Barenholz, in Methods for Biochemical Analysis, 33, D. Glick, ed., 1988. A liposome is defined as a structure consisting of one or more concentric lipid bilayers separated by water or aqueous buffer compartments. These hollow structures, which have an internal aqueous compartment, can be prepared with diameters ranging from 20 nm to 10 .mu.m. They are classified according to their final size and preparation method as: SUV, small unilamellar vesicles (0.5-50 nm); LUV, large unilamellar vesicles (100 nm); REV, reverse phase evaporation vesicles (0.5 .mu.m); and MLV, large multilamellar vesicles (2-10 .mu.m). Drug molecules can be either encapsulated in the enclosed aqueous space or intercalated into the lipid bilayer. However, the exact location of the drug in a liposome depends on its physicochemical characteristics and the composition of the lipids.
Although effective for sustained release and tissue localization of drugs, liposomes have the drawback that the amount of drug that can be contained therein is limited. Furthermore, difficulties are encountered in the preparation of pharmaceutically acceptable liposomal formulations with long term stability and high percentages of drug entrapment. A major limitation of all types of unilamellar vesicles or single bilayer liposomes is their low drug loading capacity for lipophilic compounds, due to their relatively low content of lipid molecules; therefore they are more suitable for entrapment of water-soluble materials. Although encapsulation of large amounts of hydrophobic drugs in multilamellar liposomes is feasible, they are not appropriate for intravenous administration due to their large size.
Emulsions are defined as heterogeneous systems of one liquid dispersed in another in the form of droplets usually exceeding 1 .mu.m in diameter. The two liquids are immiscible and chemically unreactive or slowly reactive. An emulsion is a thermodynamically unstable dispersed system. Instability is a result of the system's tendency to reduce its free energy by separating the dispersed droplets into two liquid phases. Instability of an emulsion during storage is evidenced by creaming, flocculation (reversible aggregation), and/or coalescence (irreversible aggregation).
The use of parenteral emulsions as drug delivery systems is still comparatively rare because of the necessity of achieving stable microdroplets of less than 1 .mu.m to prevent formation of emboli in the blood vessels. In order to increase the stability and useful lifetime of the emulsion, the dispersed lipid droplets must be coated or treated with emulsifiers or "stabilizers," which lower the free energy at the interface and decrease the tendency of droplets to coalesce. However, many emulsifiers produce deleterious side effects upon injection into the body. Due to their detergent characteristics, most of them are hemolytic agents which act as membrane solubilizers. Formulation options are severely restricted by the very limited selection of stabilizers and emulsifiers approved and safe for parenteral injection.
The water insolubility of several important drugs, such as amphotericin B, phenytoin, miconazole, cyclosporin, diazepam, and etoposide, makes their formulation for intravenous use difficult. These drugs presently are marketed in cosolvent systems such as polyethylene glycol or propylene glycol-ethanol-benzyl alcohol mixtures. However severe toxicity problems, such as thrombophlebitis, have arisen with injectable formulations of drugs dissolved in cosolvents. Alternatives to cosolvent systems are micellar solutions or emulsions; but as mentioned above, the presence of toxic surfactants in those systems makes them undesirable for intravenous administration.